Abstract

Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases.

May 28, 2014

Bertrand's class went on a field trip to Camp Kostopulos today. Camp Kostopulos is a residential summer camp where kids, teens, and adults with disabilities are able to choose from two options--a five day residential camp or travel trips. They also offer year-round recreational programs--such as horseback riding and fishing.

Bertrand (and Victoria) were able to fish with the help of student volunteers from the Open Classroom, a local charter school. The students, teachers, and parents from Open Classroom were wonderful. I think everyone from both schools had a great time. :)

Everyone called him "Indiana" since he was dressed like Indiana Jones.

May 24, 2014

With the due date of June 18, it's hard to believe that in less than a month he'll be here.

In some sense, Winston's gestation was much longer than the typical 9 months--his "conception" began almost 24 months ago in June 2012.

He is a baby that science made possible.

The process involved acronyms like IVF, PGD, CVS and many laboratories: Duke University, University of Utah, Natera, Counsyl, and GeneDx.

(And, needles. Lots of needles.)

It was a difficult process, physically and emotionally. There was a lot of anxiety, failure, and loss.

It was worth it.

We know that he isn't affected by N-glycanase deficiency--in fact, he's not even a carrier.

He is also not a carrier for 107 other rare genetic conditions.

And, he is a 100% chromosome normal XY male.

We got lucky.

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This morning, Bertrand and Victoria attended their "Sibling Preparation Class" at the hospital where mommy will deliver. The class involved anatomy posters, sibling books, baby dolls, coloring sheets, a brief video, and a hospital tour. Bertrand, being the old hand that he is, was a bit bored. Victoria was riveted and kept interrupting to lecture the teacher (a L&D nurse) on babies... and Jake and the Neverland Pirates. So, it went well. :) We are all ready and excited to meet baby Winston.

This past year, the changes that have occurred in the epilepsy community include new diagnostic tools, new treatments and more research into what causes epilepsy and what can help stop seizures. The EAU is pleased to have some of the experts in this field of study and practice, speaking at our annual Get Seizure Smart! Education Conference.

May 22, 2014

The Upsee is a "mobility device that lets children with motor impairment stand and walk with the help of an adult". It is a brand new product that is all the rage in the special needs community--and for good reason!

We've had the Upsee for over a week, and I can't say enough good things about the product or the company.

As I see it, Firefly by Leckey, the maker of the Upsee, is the Apple of special needs products. The marketing, branding, and packaging of the Upsee have all been top notch. (The unboxing of the Upsee was glorious!) More importantly, the product itself is of the highest quality, intuitive to use, and supremely effective.

At $489, the Upsee is by no means an inexpensive product but, compared to other special needs devices, it is a bargain! (A wheelchair like Bertrand's will run $8,000, and other gait devices run upwards of $3,000.)

Bertrand has really enjoyed being in the Upsee, and is building up his endurance. We plan on sending it to school with him daily so that his classmates may also benefit from using it.

May 21, 2014

Today, Bertrand's class had a field trip to Little Dell Reservoir to go canoeing courtesy of Splore, a great local organization that provides opportunities for adventure to people with physical and/or cognitive disabilities. And, an adventure it was! The entire class--including Victoria--had a fantastic time. :)

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The Bertrand Might Research Fund has been established at Sanford Burnham Medical Research Institute, a 501(c)3 charitable organization. Your donation will help Dr. Hudson Freeze’s lab begin to unravel the mystery of N-Glycanase deficiency, and hopefully find a treatment in the near future.

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Now I Can is a nonprofit 501(c)(3) charitable organization dedicated to helping disabled children reach their greatest potential through intensive physical therapy. Bertrand has benefited greatly from sessions there: Oct 2011, Dec 2011, May 2012, Aug 2012. His next session will be in July 2013.

HopeKids provides ongoing events & activities and a powerful, unique support community for families who have a child with cancer or some other life-threatening medical condition.